Each reaction step for preparing an active pharmaceutical ingredient should be a step that proceeds with a good reaction yield, is conducted with good reproducibility, can provide a high-purity product, and is thus suited for industrial production. Impurities which have appeared in each preparation process can be removed in a purification step, but a preparation process having such a purification step is not always a process suited for industrial production, because the purification step makes the work cumbersome and reduces a working efficiency. Moreover, an increase in the frequency of the purification step may reduce a total yield of a desired active pharmaceutical ingredient. There is therefore a demand for the establishment of a preparation process in which the number of purification steps is reduced as much as possible and which, as described above, proceeds with a good reaction yield, provides a high-purity product with good reproducibility, and is thus suited for industrial production.
3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2,-a][1,4]benzodiazepin-4-yl]propionic acid methyl ester benzenesulfonate is a compound having sedative and anesthetic actions.
Patent Document 1 describes a process for preparing 3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionic acid methyl ester by subjecting 3-[(S)-7-bromo-2-((R)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]-diazepin-3-yl]propionic acid methyl ester purified by recrystallization to Dess-Martin (Dess-Martin periodinane) oxidation or TEMPO (2,2,6,6-tetramethylpiperidin-N-oxyl) oxidation.
The Dess-Martin oxidation or TEMPO oxidation used in the above process is a well-known process for converting a secondary alcohol compound into a corresponding ketone compound (Non-patent Documents 1 to 4). Although Dess-Martin oxidation is capable of oxidizing a secondary alcohol compound under mild conditions, it is not completely suited for the industrial level production, because as is already known, the reagent itself is potentially explosive. On the other hand, it is said that TEMPO oxidation can be conducted under mild conditions and is an oxidation reaction ordinarily usable in the industrial level production. It has however been pointed out that TEMPO oxidation of an aromatic ring-containing compound causes chlorination of the aromatic ring as a side reaction and this problem may lead to a reduction in yield of a target compound in TEMPO oxidation (refer to Non-patent Document 5).
Thus, there is not known a industrially suited process for preparing 3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionic acid methyl ester which is a synthesis intermediate of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid methyl ester benzenesulfonate by oxidizing 3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid methyl ester, which is a raw material compound of the intended compound, safely with a high efficiency.